Estrogen receptor-related receptors: orphan receptors desperately seeking a ligand

The nuclear receptor family comprises ligand-dependent and orphan receptors. To the latter group belong the estrogen receptor-related receptors (ERRs) for which conflicting results have been published concerning the nature (constitutive or liganded) of their transcriptional activities. ERRs interfere in various ways, positively and negatively, with estrogen signaling. Moreover recent data analyzing ERR expression in human breast tumors have proposed ERRalpha and ERRgamma as prognostic markers of these cancers. The identification of modulators (positive or negative) of ERR activities would therefore be highly useful in our understanding of estrogen-related pathologies. The purpose of this review is to summarize our knowledge of the nature of ERR activities and progresses in identifying synthetic ERR modulators.